PROJECT 2 - PROJECT SUMMARY/ABSTRACT Insulin resistance (IR) and central obesity at midlife are associated with cognitive decline and greater risk for developing Alzheimer's disease (AD). Converging evidence suggests amyloid and neural injury mediate this effect. Yet, the impact of IR and central obesity on the brain remains poorly understood in humans, especially at the preclinical stage of the disease. The objective of Project 2 is to determine the effect of IR and central obesity on longitudinal brain and cognitive change in people at risk for AD. Our overall hypothesis is that central obesity and IR affect multiple pathways which ultimately contribute to a critical burden of neural pathology manifesting as cognitive decline. Our hypothesis is based on our own pilot data (presented herein) showing that central obesity and IR affect amyloid deposition, gray matter atrophy, glucose metabolism, and memory function. To carry out our objective and test our hypothesis, we propose 3 Specific Aims: 1) Determine the extent to which IR and central obesity are linked with midlife beta amyloid, 2) determine the effect of IR and central obesity on neural health in late-midlife, and 3) determine the mediating effect of amyloid and neural injury on memory function. We will achieve these aims by enrolling 100 participants from the Wisconsin ADRC IMPACT cohort into Project 2. The IMPACT cohort is an asymptomatic group of middle-aged adults enriched on risk for AD. We will utilize existing data and samples, in addition to prospectively collected MRI (T1- weighted), CSF (to be assayed for P-Tau, A42, sAPP-, and insulin) cognitive, laboratory and clinical data; culminating in at least three time points. Half of the participants in Project 2 will be enrolled into a PET sub- study and will undergo [F18]FDG-PET, and [F18]Florbetapir imaging at two time points. Following completion of this study, we will have a) determined the extent to which IR and central obesity affect the -secretase pathway of APP cleavage, and longitudinal amyloid deposition, b) determined the effect of IR and central obesity on longitudinal brain amyloidosis as indexed by [F18]Florbetapir, c) determined the effect of IR and central obesity on structural neural injury and glucose uptake, d) determined whether glucose hypometabolism is due to neural injury or central hypoinsulinemia, and e) determined the extent to which amyloid and neural injury mediate the relationship between IR, central obesity, and hippocampal-based memory decline. The proposed research is fully integrated with the resources and expertise at the Wisconsin ADRC. This project depends on the Clinical Core (IMPACT cohort) and the Neuropathology Core (fluid sample management), and will utilize other resources including services provided by the Neuroimaging Core and the Data Management and Statistics Core. Synergy with the Wisconsin ADRC ensures the strong feasibility of the proposed research. The metabolic abnormalities to be studied in Project 2 affect more than half of all older adults, while also being established AD risk factors that have the potential to be modified. Understanding the mechanisms that impact trajectories of brain and cognitive aging is expected to lead to strategies that delay and prevent AD.